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11/30/2015 Chapter 21: Genomes & Their Evolution 1. Sequencing & Analyzing Genomes 2. How Genomes Evolve 1. Sequencing & Analyzing Genomes Chapter Reading – pp. 437-447 Whole Genome Shotgun Sequencing 1 Cut the DNA into overlapping fragments short enough for sequencing. 2 Clone the fragments in plasmid or phage vectors. 3 Sequence each fragment. 4 Order the sequences into one overall sequence with computer software. 1 11/30/2015 Bioinformatics Bioinformatics refers to application of statistics and computer analysis to DNA, protein sequence data. • computer analysis can identify protein coding regions in DNA, determine amino acid sequences, compare sequences among species, etc… Systems Level Analysis Translation and ribosomal functions Glutamate biosynthesis Mitochondrial functions Vesicle fusion RNA processing Peroxisomal functions Transcription and chromatinrelated functions Metabolism and amino acid biosynthesis Nuclearcytoplasmic transport Secretion and vesicle transport Nuclear migration and protein degradation Mitosis DNA replication and repair Cell polarity and morphogenesis Protein folding, glycosylation, and cell wall biosynthesis Serinerelated biosynthesis Amino acid permease pathway Computer analysis can predict protein/protein interactions and thus protein function. Relative Genome Size Genome size and gene number do not correlate at all with organism complexity. • alternative splicing of genes and the repertoire of noncoding RNAs (e.g., miRNA) may be a better indicator of “sophistication” or complexity in a species 2 11/30/2015 Types of Human DNA Elements Most of the human genome (and that of many other species) does not code for any obvious gene products and has a function that is as yet unclear. Repetitive DNA Elements Much of the human genome consists of repetitive DNA sequences that are thought to ultimately be of viral origin. Transposable Elements • DNA segments that are duplicated and distributed throughout the genome Alu elements • repetitive DNA sequences containing the Alu I restriction enzyme sites Short tandem repeats (STRs) • very short sequences repeated over and over Transposable Elements Barbara McClintock proposed the concept of “jumping genes” in the 1950s based on her studies of corn which was not taken seriously. Much later the existence of transposable elements that could “jump” in the genome validated her observations. 3 11/30/2015 Transposons Transposon DNA of genome New copy of transposon Transposon is copied Insertion Mobile transposon Mobile DNA elements that can be copied & inserted Elsewhere in the genome. • the transposon encodes the enzyme transposase which can copy transposon sequence and randomly insert elsewhere Retrotransposons Retrotransposons are much like transposons except that they encode reverse transcriptase and have an RNA intermediate in the process. New copy of Retrotransposon retrotransposon Formation of a single-stranded RNA intermediate RNA Insertion Reverse transcriptase Multigene Families Many genes are actually part of a group or cluster of similar genes referred to as a “multigene family”. • 2 or more genes with nearly identical or very similar sequences • thought to have arisen due to gene duplication and subsequent mutation • members of a multigene family are typically similar in function as well as sequence • arrangement of genes in multigene families also provides evidence of similar origins 4 11/30/2015 DNA RNA transcripts Nontranscribed spacer Transcription unit DNA 18S 28S 5.8S rRNA 5.8S 28S 18S (a) Part of the ribosomal RNA gene family -Globin -Globin Heme -Globin gene family -Globin gene family Chromosome 11 Chromosome 16 Embryo 2 1 2 1 Fetus and adult Embryo G A Fetus Adult (b) The human -globin and -globin gene families 2. How Genomes Evolve Chapter Reading – pp. 448-458 5 11/30/2015 Rearrangement of Genomes Genomes can undergo a number of large-scale changes that can lead to significant changes in genetic structure and in gene products: Chromosomal rearrangement • breaking and recombining of pieces of diff. chrom. Transposition of mobile DNA elements • sequences that can move around the genome Gene duplication • duplication of gene sequences Exon shuffling • combining of exons from different genes Changes in Chromosome Structure Human chromosome 2 is clearly a combination of chimpanzee chromosomes 12 & 13. Human chromosome 2 Chimpanzee chromosomes Telomere sequences Centromere sequences Telomere-like sequences 12 Human chromosome 16 Centromere-like sequences 13 (a) Human and chimpanzee chromosomes Blocks of genes in mice and humans have remained intact though they are distributed differently among chromosomes. Mouse chromosomes 7 8 16 17 (b) Human and mouse chromosomes Evolution of Novel Genes Genes encoding proteins with entirely new functions can arise by: 1) Duplication of existing gene followed by mutation producing distinct gene product • the 2 genes will share significant homology however may have very different functions (e.g., lysozyme and -lactalbumin) 2) Exon shuffling • errors in meiotic recombination or transposition can cause the addition or loss of exons from similar or very different genes 6 11/30/2015 Gene Duplication & Crossing Over Nonsister Gene chromatids Transposable element Misalignment of similar DNA sequences during meiotic crossing over can result in chromosomes with duplicated (or missing) regions of DNA. Crossover point Incorrect pairing of two homologs during meiosis and Duplication followed by Mutation lysozyme vs -lactalbumin Model for Globin Gene Duplication The globin gene families show evidence of duplication. Ancestral globin gene Evolutionary time Duplication of ancestral gene Mutation in both copies Transposition to different chromosomes Further duplications and mutations 2 1 2 1 -Globin gene family on chromosome 16 G A -Globin gene family on chromosome 11 7 11/30/2015 Globin Gene Comparison Over time apparently duplicated globin genes diverged via mutation into similar yet distinct proteins with similar yet unique functions. Exon Shuffling EGF EGF EGF EGF Epidermal growth factor gene with multiple EGF exons F F F Exon shuffling Exon duplication F Fibronectin gene with multiple “finger” exons F EGF K K K Exon shuffling Plasminogen gene with a “kringle” exon Portions of ancestral genes TPA gene as it exists today Comparing Genomes Bacteria Most recent common ancestor of all living things Eukarya Archaea 4 1 3 2 Billions of years ago 0 Chimpanzee Human Mouse 70 60 50 40 30 20 10 0 Sequence homology and genome structure reflect evolutionary relatedness: • degree of differences in gene sequences, chromosome & gene structures allow estimation of time since a common ancestor Millions of years ago 8 11/30/2015 Gene Knockout Experiments For the last 20 or so years we have had the technology to disrupt or “knockout” genetic alleles in mice to assess gene function: 1) mouse embryonic stems cells (ES cells) are genetically altered in vitro • specific gene is targeted for disruption and ES cells with disrupted gene are selected for 2) disrupted ES cells added to early embryos which are implanted into surrogate mothers 3) offspring are screened for “knockout” allele 4) positive offspring are mated to produce homozygous knockouts for analysis of gene function A Gene Knockout EXPERIMENT Wild type: two normal copies of FOXP2 Heterozygote: one copy of FOXP2 disrupted Homozygote: both copies of FOXP2 disrupted Experiment 1: Researchers cut thin sections of brain and stained them with reagents that allow visualization of brain anatomy in a UV fluorescence microscope. mice don’t “whistle” (i.e., vocalize) when stressed*. Foxp2-/- RESULTS Experiment 2 Number of whistles Experiment 1 Experiment 2: Researchers separated each newborn pup from its mother and recorded the number of ultrasonic whistles produced by the pup. Wild type Heterozygote 400 300 200 100 Homozygote *FOXP2 must be necessary for assoc. brain develop. Homeotic Genes Homeotic genes were first discovered in Drosophila to specify body segments. Homologous genes arranged in same fashion have been identified in mammals and other animals as well as yeast & plants • Hox gene clusters or families in animals (No whistles) 0 Wild type Heterozygote Homozygote Adult fruit fly Homeotic genes encode TFs Fruit fly embryo (10 hours) Fly chromosome Mouse chromosomes Mouse embryo (12 days) Adult mouse 9 11/30/2015 Differential Hox Gene Expression Thorax Genital segments Thorax Abdomen Abdomen Differences in Hox gene expression result in different specification of body segments and thus different overall body plans among species! Key Terms for Chapter 21 • 3-step genome vs whole genome shotgun seq. • bioinformatics, genomics, proteomics • transposable elements: transposons , transposase, retrotransposons • gene duplication, exon shuffling • gene knockouts, knockout mice, ES cells • homeotic genes, Hox genes Relevant Chapter Questions 1-6 10